Package form for bicarbonate-containing powdery pharmaceutical compositions and a method of stabilizing the compositions

ABSTRACT

The invention provides a method and a package form for insuring a stabilized bicarbonate-containing pharmaceutical composition, the method comprises filling the bicarbonate-containing powdery pharmaceutical composition in a moisture- and gas-permeable plastic container, wrapping the so-filled container in a moisture- and gas-impermeable plastic wrapper and carrying out at least one procedure selected from the group consisting of the procedure of introducing a carbon dioxide gas into a space between the container and wrapper, the procedure of disposing a carbon dioxide-liberating deoxygenating agent in the space and the procedure of disposing a desiccant previously saturated with carbon dioxide gas by way of adsorption in the space. In accordance with the invention, the inherent objects of incorporating the bicarbonate can be accomplished without inducing the aging and degradation of the bicarbonate-containing powdery pharmaceutical composition.

TECHNICAL FIELD

The present invention relates to a method of stabilizing abicarbonate-containing powdery pharmaceutical composition, particularlya novel method of stabilizing a bicarbonate-containing powderypharmaceutical composition which allows the composition in a plasticcontainer to remain wholesome without aging or degradation and theobject of addition of the carbonate to be accomplished withoutcompromise and to a package form for such bicarbonate-containing powderypharmaceutical composition.

BACKGROUND ART

With very few exceptions such as sodium chloride, drugs are susceptibleto aging loads such as water, oxygen and light and glass ampules havebeen in use for their storage since many years ago. However, with therecent advances in pharmaceutical science, material engineering,production methodology, production equipment, etc., these pharmaceuticalcontainers are being replaced by glass vials and plastic (such aspolyolefins, e.g. polyethylene, polypropylene, etc., ethylene-vinylacetate copolymer, polyethylene terephthalate, polyvinyl chloride, etc.)containers which are easy for those engaged in medical practice tohandle and easy to dispose of after use and the utilization of suchplastic containers, in particular, is rapidly spreading of late.

However, unlike glass, plastics are inherently permeable to gas andmoisture and have the disadvantage that containers made thereof cannotbe used for all kinds of drugs. Recently, materials which are almost asimpervious to gas and moisture as glass, such as a laminate filmcarrying a vapor-deposited aluminum layer or an aluminum foil, alaminate film carrying a vapor-deposited silicon monoxide layer, amulti-layer film consisting of plural materials such as polyethyleneterephthalate, polyvinyl alcohol, polyvinylidene chloride,ethylene-vinyl alcohol copolymer, etc. have been developed and todayplastics with an oxygen permeability rate of not more than 1.0 cc/m² ·24hrs/1 atm. and a moisture permeability rate of not more than 1.0 g/m²·24 hrs/1 atm. are available on the market and finding ever broadeningusage and application.

Meanwhile, drugs are generally stable in the bulk form but if they aredissolved and administered to patients, the low pH values of thesolutions would not only damage the local tissue at the administrationsite but also induce systemic disturbances or result in poor absorption.Therefore, a variety of pharmaceutical contrivances has so far been madeto avoid the troubles. By way of illustration, assuming that thepharmaceutical composition contains a strongly acidic powdery substancesuch as the hydrochloride or an acidic powdery drug whose neutral saltwould be unstable, it is common practice to formulate the drug with abicarbonate to insure the proper pH on dissolution or convert it to theneutral salt which is more readily absorbed at the time ofadministration.

Moreover, drugs which are unstable in solution, for example certainantibiotics, are supplied in the powdery form but since these drugs ingeneral are sparingly soluble in aqueous vehicles, a bicarbonate as asource of carbon dioxide gas, which assists in dissolution, is added asa solubilizer.

On the other hand, sodium hydrogen carbonate is contained as analkalizing agent in dialysis fluid compositions for artificial kidneyuse and for the purpose of insuring the ease of handling and reducingthe cost of shipment, the recent tread is toward converting such liquidcompositions to powdery or granular preparations (e.g. Japanese PatentApplication Kokai H3-38527 and Kokai H3-74331).

The bicarbonate contained in such pharmaceutical compositions liberateswater and carbon dioxide gas with time but it is well known that in aclosed system there is established an equilibrium among the bicarbonate,carbonate, water and carbon dioxide as indicated by the followingrelation (1).

    2HCO.sub.3.sup.- ⃡CO.sub.3.sup.2- +H.sub.2 O+CO.sub.2( 1)

However, when a bicarbonate-containing powdery pharmaceuticalcomposition is supplied in a plastic (such as polyolefins, e.g.polyethylene, polypropylene, etc., ethylene-vinyl acetate copolymer,polyvinyl chloride, etc.) container, the carbon dioxide gas and waterliberated from the bicarbonate find their way out through the plasticcontainer which is permeable to gas and moisture. As a result, thebalance of the above relation (1) is tipped to the right to yield thecarbonate so that when the composition is dissolved for administration,the intrinsic objects of adding the bicarbonate, namely supply of HCO₃⁻, neutralization of the drug, and assistance in dissolution, cannot beaccomplished. Moreover, the solution after reconstitution undergoesincrease of pH to affect the stability of the drug solution. For theprotection of a powdery pharmaceutical composition containing a drugliable to decompose on absorption of moisture and a bicarbonate, assupplied in a plastic container, from the decomposition due to moisture,it might be contemplated to dispose a desiccant externally of theplastic container and wrapping the plastic container and desiccanttogether in a wrapping material with proven performance qualities, e.g.an oxygen permeability rate of not more than 1.0 cc/m² ·24 hrs/ 1 atm.and a water permeability rate of not more than 1.0 g/m² ·24 hrs/1 atm.,such as a laminate film carrying a vapor-deposited silicon oxide layer,a composite laminate film comprising a plurality of materials such aspolyethylene terephthalate, polyvinyl alcohol, polyvinylidene chloride,ethylene-vinyl alcohol copolymer, etc. or a laminate film having avapor-deposited aluminum layer or an aluminum foil which is equivalentto glass in barrier performance. In such cases, there still occur eventssimilar to those encountered when a bicarbonate-containing powderycomposition is simply filled into a plastic container. Thus, the waterand carbon dioxide gas liberated from the bicarbonate are adsorbed onthe included desiccant so that the balance of said relation (1) istipped to the right to cause the formation of carbonate and, hence, anelevation of pH of the solution after reconstitution.

The present invention provides a new technology which overcomes all theabove-mentioned problems associated with the provision of abicarbonate-containing powdery pharmaceutical preparation in a plasticcontainer which is permeable to moisture and gas by insuring anincreased carbon dioxide concentration in the container, allowing themoisture to be dissipated to the extent not affecting the quality of thedrug, and inhibiting decomposition of the bicarbonate and formation ofthe carbonate to suppress the increase of pH after reconstitution andallow the inherent objects of incorporation of the carbonate, namelysupply of HCO₃ ⁻, neutralization of the drug and assistance indissolution, to be accomplished without compromise.

DISCLOSURE OF INVENTION

In accordance with the present invention there is provided a method ofstabilizing a bicarbonate-containing powdery composition characterizedin that the placement of a bicarbonate-containing powdery pharmaceuticalcomposition in a plastic container permeable to moisture and gas isfollowed by at least one procedure selected from among the procedure ofintroducing carbon dioxide gas into a space between the container and awrapper and the procedure of disposing a carbon dioxide-liberatingdeoxygenating agent in said space and the procedure of disposing adesiccant previously saturated with carbon dioxide gas by way ofadsorption, particularly such a method of stabilizing abicarbonate-containing powdery pharmaceutical composition for dialysis.

The present invention further provides the above stabilizing methodwherein not only a carbon dioxide-liberating deoxygenating agent butalso a desiccant is disposed in said space between the container andwrapper, which is applicable with particular advantage to the case inwhich said bicarbonate-containing powdery pharmaceutical composition isan antibiotic-containing composition.

The invention further provides a method of stabilizing abicarbonate-containing powdery pharmaceutical composition characterizedby filling the bicarbonate-containing powdery composition into a plasticcontainer which is impermeable to moisture and gas and introducingcarbon dioxide gas into said container, which method is applicable withparticular advantage to the case in which said bicarbonate-containingpowdery pharmaceutical composition is a powdered dialysate.

Furthermore, the present invention provides a package form contributoryto the stabilization of a bicarbonate-containing powdery pharmaceuticalcomposition which comprises a plastic container permeable to moistureand gas and adapted to contain the bicarbonate-containing powderypharmaceutical composition and a plastic packaging wrapper asimplemented by following at least one procedure selected from the groupconsisting of the procedure of filling the space between said containerand wrapper with carbon dioxide gas, the procedure of disposing a carbondioxide gas-liberating deoxygenating agent in said space and theprocedure of disposing a desiccant saturated with carbon dioxide gas byway of adsorption in said space.

The moisture- and gas-permeable plastic container used for accommodatinga bicarbonate-containing powdery pharmaceutical composition for the useof the present invention may be made of various materials which arepermeable to moisture and gas including but not limited to polyolefinssuch as polyethylene, poly-propylene, ethylene-α-olefin copolymers,etc., ethylene-vinyl acetate copolymer, polyvinyl chloride, polyamides,etc., inclusive of multi-layer films comprising such materials invarious combinations.

The moisture- and gas-impermeable plastic wrapper for use in the presentinvention includes, among others, moisture- and gas-impermeablealuminum-laminated films, laminate films carrying a vapor-depositedaluminum or silicon monoxide layer and multi-layer films comprising suchmaterials as polyethylene terephthalate, polyvinyl alcohol,polyvinylidene chloride, ethylene-vinyl alcohol copolymer, etc. insuitable combinations. Among the various materials mentioned above,transparent materials through which the contents of the container can bevisually inspected, such as a laminate film carrying a vapor-depositedsilicon monoxide layer or a multi-layer film comprising a combination ofpolyethylene terephthalate, polyvinyl alcohol, polyvinylidene chloride,ethylene-vinyl alcohol copolymer and/or the like, are preferred.

The bicarbonate for use in the present invention includes sodiumhydrogen carbonate, potassium hydrogen carbonate, ammonium hydrogencarbonate and other bicarbonates. As representative examples of saidbicarbonate-containing powdery pharmaceutical composition may bementioned various powdery preparations for dialysis use (powdereddialysate preparations for artificial kidney use and powderypreparations for peritoneal dialysis) and antibiotic preparations.

The antibiotics for use as active ingredients of saidantibiotic-containing pharmaceutical compositions may be any knownantibiotics such as cephalosporins antibiotics, e.g. cefazolin sodium,ceftizoxime sodium, cefotiam hydrochloride, cefmenoxime hydrochloride,cefacetrile sodium, cefamandole sodium, cefaloridine, cefotaxime sodium,cefotetan sodium, cefoperazone sodium, cefsulodin sodium, ceftezolesodium, cefpiramide sodium, cefmetazole sodium, cefuroxime sodium,ceftazidime, etc., penicillin antibiotics such as ampicillin sodium,carbenicillin sodium, sulbenicillin sodium, ticarcillin sodium,cloxacillin sodium, piperacillin sodium, etc., monobactam antibioticssuch as carumonam sodium, and carbapenem antibiotics such as imipenemand so on.

In the present invention which comprises introducing carbon dioxide gasinto the space between said container accommodating abicarbonate-containing powdery pharmaceutical composition and saidwrapper, disposing a carbon dioxide gas-liberating deoxygenating agentin said space or disposing a desiccant saturated with carbon dioxide gasby way of adsorption in said space, the concentration of carbon dioxidegas in the container can be maintained at the proper level. Forstabilizing a hygroscopic pharmaceutical composition, a desiccant can befurther disposed in said space to attain a more satisfactory stabilizingeffect.

The present invention may also be carried into practice by using amoisture- and gas-impermeable plastic container and filling a powderypharmaceutical composition, such as a powdered dialysate composition,directly into the container. In this mode, the object of the inventioncan be accomplished by filling carbon dioxide gas in the container.However, the carbon dioxide gas-liberating deoxygenating agent and thedesiccant adsorptively saturated with carbon dioxide gas cannot bedisposed in the container because it would result in a direct contact ofthem with the bicarbonate-containing powdery composition.

Filling of the container with carbon dioxide gas can be carried out byany of the conventional methods. For example, when said wrapper isemployed, the space between the wrapper and the plastic container can befilled with carbon dioxide gas or a mixture gas of carbon dioxide andnitrogen. When a container impermeable to moisture and gas is employed,the container may be filled with carbon dioxide gas or said mixture gasin the same manner. In either procedure, it is preferable to evacuatethe air from the container beforehand, i.e. preceding said filling withcarbon dioxide gas.

The carbon dioxide gas-liberating deoxygenating agent which can be usedin the present invention can be any substance having both deoxygenatingand carbon dioxide gas-liberating activities but is preferably asubstance which is capable of removing oxygen from said space andinsuring a high output of carbon dioxide gas. Such deoxygenating agentincludes those which contain, as the principal active ingredient, atleast one member selected from the group consisting of iron powder;reducing inorganic salts such as dithionites, sulfites, ferrous salts,etc.; polyphenols such as hydroquinone, catechol, etc., reducingpolyhydric alcohols such as ascorbic acid, erythorbic acid and theirsalts. The dithionites absorb oxygen in the presence of water and, atthe same time, react with a bicarbonate or carbonate to yield carbondioxide gas. The agents comprising sodium ascorbate and ferrous sulfateas main ingredients absorb oxygen and generate carbon dioxide gas in thepresence of water. Commercial products among such carbon dioxidegas-liberating deoxygenating agents include Ageless G (registeredtrademark, Mitsubishi Gas Chemical) and Sendo-Hojizai (Keep-Fresh) TypeC (Toppan Printing), among others.

The desiccant saturated with carbon dioxide gas for use in the presentinvention includes silica gel, various aluminum silicates, crystallinehydrated alkali metal or alkaline earth metal aluminosilicates andzeolites which have been saturated with carbon dioxide gas by way ofadsorption. To let said desiccant adsorb carbon dioxide gas tosaturation, the desiccant is allowed to stand in a carbon dioxideatmosphere at room temperature or a lower temperature, preferably nothigher than about 15° C., for several hours. For example, when thecommercial product Zeolum (registered trademark) A4 (Tosoh), issubjected to the above procedure, the desired desiccant saturated withcarbon dioxide gas is easily obtained. Zeolum (registered trademark)A3RG (Tosoh), which is comparatively low in carbon dioxide adsorptionpotential, can also be saturated with carbon dioxide gas in the samemanner. When the desiccant saturated with carbon dioxide gas is disposedin the space between the plastic container and wrapper, carbon dioxidegas is liberated from the desiccant saturated with carbon dioxide gas sothat a carbon dioxide atmosphere is established within the space.Moreover, since such desiccant has a high adsorptive affinity for watervapor than carbon dioxide gas, it adsorbs not only moisture and adherentwater from the powdery pharmaceutical composition within the plasticcontainer but, depending on conditions, the water which may be liberatedby decomposition of the bicarbonate for some cause or other to releasecarbon dioxide gas so that the carbon dioxide partial pressure withinthe container is elevated to inhibit decomposition of the bicarbonate.

It should be understood that when the relative humidity in the containeris to be maintained at a level not exceeding 1% at 25° C. in the presentinvention, zeolites having high dehydrating agents are preferablyemployed.

In the present invention, a desiccant saturated with carbon dioxide gasand a deoxygenating agent which absorbs oxygen by way of oxidationreaction, such as said iron powder, dithionites, sulfites, ferroussalts, etc., can be used in combination. In this mode, when amoisture-containing self-reacting type deoxygenating agent (e.g. AgelessZ from Mitsubishi Gas Chemical) is used as said deoxygenating agent, thecarbon dioxide concentration and moisture level within the container canbe adequately maintained without causing degradation of thebicarbonate-containing powdery pharmaceutical composition.

In the present invention, a carbon dioxide gas-liberating deoxygenatingagent and a desiccant can be used in combination. In this mode, the useof a moisture-containing carbon dioxide gas-liberating deoxygenatingagent is particularly preferred. Thus, when such a moisture-containingcarbon dioxide gas-liberating deoxygenating agent is used in combinationwith a desiccant, the deoxygenating agent releases traces of water andthe desiccant is prevented from adsorbing carbon dioxide gas owing tothe preferential adsorption of such traces of water so that the carbondioxide gas in the space is maintained at a suitable concentrationlevel. The use of said carbon dioxide gas-liberating deoxygenating agentis also beneficial when the bicarbonate-containing powderypharmaceutical composition is a composition susceptible to oxidativedecomposition.

Thus, in accordance with the present invention, thebicarbonate-containing powdery pharmaceutical composition can bepreserved in a plastic container without aging and degradation and, atthe same time, the object of addition of the bicarbonate can beaccomplished without compromise.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a schematic sectional view showing a typical package form ofthe invention as obtained in Example 1 which appears hereinafter.

In the view, (1) stands for a plastic wrapper, (2) for a plasticcontainer, (3) for a bicarbonate-containing powdery pharmaceuticalcomposition, and (4) for a carbon dioxide gas-liberating deoxygenatingagent.

BEST MODE OF PRACTICING THE INVENTION

The following examples are intended to illustrate the invention infurther detail. The materials used in the examples are referred to bythe following abbreviations.

    ______________________________________                                        L-LDPE        Linear low-density polyethylene                                 KPET          Polyvinylidene chloride-coated                                                polyethylene terephthalate                                      PVDC          Polyvinylidene chloride                                         ______________________________________                                    

Example 1

A bag (175 μm thick, 50×50 mm) made of L-LDPE (density 0.920) was filledwith 20 mg of sodium hydrogen carbonate and 100 mg of sodium chloride.Then, this filled bag and one piece of the carbon dioxide gas-liberatingoxygenating agent (Ageless G15, Mitsubishi Gas Chemical) were placed ina laminate-film wrapping bag of KPET (15 μm)/PVDC (25 μm)/L-LDPE (30 μm)(sized 70×70 mm), followed by heat sealing to provide a container of theinvention as illustrated in FIG. 1. This product is used for a carbondioxide gas-liberating deoxygenating agent group.

Similarly an L-LDPE bag containing said drugs was prepared and placed inthe same wrapping bag as above. This was followed by filling with amixture gas of 5%, 10% or 20% of carbon dioxide gas and the balance ofair and the wrapping bag was heat-sealed. This was used for a carbondioxide-filled group. As a control, the same L-DPE bag containing thedrugs, not packaged in the wrapping bag, was tested. This was used for acontrol group.

The samples in the above CO₂ -liberating deoxygenating agent group, CO₂gas-filled group and control group were stored at 40° C. and 75% RH. Thesamples immediately after manufacture and after storage periods of 1, 2and 3 months were respectively dissolved in 100 ml of physiologicalsaline and the pH of each solution was measured. The results are shownin Table 1.

                  TABLE 1                                                         ______________________________________                                                             Storage at 40° C. and                                         Immediately                                                                            75% RH                                                                 after      1       2     3                                      Sample groups manufacture                                                                              Month   Months                                                                              Months                                 ______________________________________                                        CO.sub.2 gas-liberating                                                                     8.02       8.05    8.02  8.03                                   deoxygenator group                                                            CO.sub.2 gas-filled group                                                     CO.sub.2 concentration 5%                                                                   8.02       8.05    8.07  8.04                                   CO.sub.2 concentration 10%                                                                  8.02       8.03    8.02  8.05                                   CO.sub.2 concentration 20%                                                                  8.04       8.03    8.05  8.02                                   Control       8.03       8.23    8.47  8.69                                   ______________________________________                                         Each value is the mean of n = 3                                          

It is apparent from Table 1 that the solutions from the carbondioxide-liberating deoxygenator group and carbon dioxide gas-filledgroup showed no pH elevation, indicating that the use of a carbondioxide gas-liberating deoxygenating agent and the procedure of fillingwith carbon dioxide gas, both according to the invention, arresteddecomposition of the bicarbonate in the plastic container.

While a mixed powder of sodium hydrogen carbonate and sodium chloridewas used as the bicarbonate-containing powdery pharmaceuticalcomposition in this example, the method described in this example of theinvention can be applied with advantage to any other powdery compositioncomprising a varying type of electrolyte other than sodium chloride incombination with sodium hydrogen carbonate, for example a powdereddialysate composition.

Example 2

A laminate film bag of KPET (15 μm)/PVDC (25 μm)/L-LDPE (30 μm) (sized90×90 mm) was filled with 20 mg of sodium hydrogen carbonate and 100 mgof sodium chloride. The bag was then filled with a mixture gas of 5%,10% or 20% of carbon dioxide gas and the balance of air and heat-sealedto provide a package form of the invention.

The above package form was stored at 40° C./75% RH and samplesimmediately after manufacture and after storage periods of 1, 2 and 3months were respectively dissolved in 100 ml of physiological saline andthe pH of each solution was measured.

As a result, the solution from the above package form was as stable asthat in the CO₂ gas-filled group of Example 1. Moreover, the method andpackage form described in this example were suited for powdereddialysate compositions.

Example 3

Using a pharmaceutical composition (hereinafter referred to as Drug A)comprising one gram (potency) of a crystalline powder of cefalexin(hereinafter referred to as CEX), a cephem antibiotic, and 20 mg ofsodium hydrogen carbonate, the following experiment was carried out.

Thus, Drug A was filled into a glass vial (.o slashed.26 mm, NichidenRika Glass), stoppered with a butyl rubber stopper and clinched with analuminum band (Sample 1, control).

Then, Drug A was filled into a bag (175 μm thick, 50×50 mm) made ofL-LDPE (density 0.920) and the filled bag was placed in a laminate-filmwrapping bag of KPET (15 μm)/PVDC (50 μm)/L-LDPE (50 μm) (sized 70×70mm) and heat-sealed (Sample 2, comparative example). Samples wereprepared in the same manner except that 6 g of silica gel (Fuji GelIndustry) was inserted before said heat-sealing (Sample 3, comparativeexample), 2 g of a zeolite (Zeolum A4, Tosoh) was placed before saidheat-sealing (Sample 4, comparative example), 2 g of a zeolite (ZeolumA3RG, Tosoh) previously saturated with carbon dioxide gas was inserted(Sample 5, this invention), 2 g of a zeolite (Zeolum A3RG, Tosoh) andone piece of a CO₂ gas-liberating deoxygenating agent (Ageless G20,Mitsubishi Gas Chemical) were inserted (Sample 6, this invention), and 2g of a zeolite (Zeolum A4, Tosoh) and one piece of a CO₂ gas-liberatingdeoxygenating agent were inserted (Ageless G20, ditto) (Sample 7, thisinvention).

The above samples were stored at 40° C. and 75% RH.

In a preliminary experiment in which the respective samples were storedat 40° C. and 75% RH, elevations of pH were observed after 2 months ofstorage at 40° C./75% RH. Based on this result, the samples prior to thebeginning of storage and those after 3 months of storage were examinedfor the pH of Drug A (as dissolved in 100 ml of physiological saline),water content, potency (calculated on the anhydrous basis), carbondioxide concentration in the bag, and appearance (color).

The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                                          CO.sub.2 -                                                                    liberating                                  No.  Container      Desiccant     deoxygenator                                ______________________________________                                        1    Glass vial +   --            --                                               rubber stopper                                                           2    Plastic bag +  --            --                                               laminate film wrapper                                                    3    Plastic bag +  Silica gel, 6 g                                                                             --                                               laminate film wrapper                                                    4    Plastic bag +  Zeolum A4, 2 g                                                                              --                                               laminate film wrapper                                                    5    Plastic bag +  Zeolum A3RG*, 2 g                                                                           --                                               laminate film wrapper                                                    6    Plastic bag +  Zeolum A3RG, 2 g                                                                            Ageless G20                                      laminate film wrapper                                                    7    Plastic bag +  Zeolum A4, 2 g                                                                              Ageless G20                                      laminate film wrapper                                                    ______________________________________                                        Before storage                                                                                     Potency of                                                                    antibiotic                                                           Moisture (μg   CO.sub.2 con-                                               content  (potency)/                                                                             centration                                      No.  pH     (%)      mg)      (ppm)   Appearance                              ______________________________________                                        1    7.24   4.35     994      291     White                                   2    7.28   4.27     1018     275     White                                   3    7.32   4.11     1001     230     White                                   4    7.30   4.24     1031     0       White                                   5    7.31   4.18     992      254     White                                   6    7.26   4.20     1007     2825    White                                   7    7.25   4.21     1012     0       White                                   ______________________________________                                        After 3 months of storage at 40° C./75% RH                                                  Potency of                                                                    antibiotic                                                           Moisture (μg   CO.sub.2 con-                                               content  (potency)/                                                                             centration                                      No.  pH     (%)      mg)      (ppm)   Appearance                              ______________________________________                                        1    7.26   4.34     998      2141    White                                   2    6.35   5.15     723      2180    Pale                                                                          yellow                                  3    7.80   4.15     1009     824     White                                   4    8.02   4.18     1002     0       White                                   5    7.43   4.14     1015     1521    White                                   6    7.18   4.22     999      9891    White                                   7    7.23   4.15     1002     7368    White                                   ______________________________________                                         Zeolum A3RG* in Sample No. 5 in Table 2 was previously saturated with         carbon dioxide gas.                                                      

Referring to the combination of an L-LDPE container and a laminate filmwrapper, Sample 2 (comparative example) which contained neither of thedesiccant and carbon dioxide gas-liberating deoxygenating agent wasaffected by external moisture to show a decrease in potency of theantibiotic and a change in appearance. The pH was also fairly depressedand it was considered attributable to decomposition products of CEX.

Sample 3 (comparative example) which contained a silica gel having nohigh desiccating power showed no loss of potency or an increase inmoisture content because CEX is not so hygroscopic. However, the pH ofits solution showed an increase of about 0.5 from the value prior tostorage. The cause of this increase is that because the desiccantadsorbed moisture, the sodium hydrogen carbonate was partiallydecomposed to sodium carbonate.

Sample 4 (comparative example) in which Zeolum A4, a potent desiccant,was used, there was no decrease in potency but because of the markedadsorption of carbon dioxide gas on the desiccant, the pH exceeded 8 at3 months of storage, an increase of about 0.7. This result suggestedthat the use of a potent desiccant alone is not effective enough for thestabilization of powdery antibiotic products.

On the other hand, Sample 5, Sample 6 and Sample 7 (all of theinvention) showed findings comparable to those of Sample 1 (control)employing the glass vial which is the ordinary container forantibiotics, in potency, moisture level and pH.

Sample 5, in which the low CO₂ -adsorbing Zeolum A3RG was previouslysaturated with carbon dioxide gas, showed a lesser change of pH and noremarkable difference in carbon dioxide concentration as compared withSample 1.

On the other hand, Sample 6 and Sample 7, in which a CO₂ -liberatingdeoxygenating agent was employed, showed somewhat higher CO₂concentrations than Sample 1 and Sample 5 but no changes of significancein potency, moisture level and pH.

Thus, the bicarbonate-containing pharmaceutical composition in a plasticcontainer could be well maintained by means of a moisture- andgas-impermeable wrapper, a desiccant and a carbon dioxide gas-liberatingdeoxygenating agent without causing the aging and degradation of theactive ingredient(s) and without inducing the formation of carbonatefrom bicarbonate.

INDUSTRIAL APPLICABILITY

The method of the present invention for stabilizing abicarbonate-containing powdery pharmaceutical composition insures anincreased carbon dioxide gas concentration in the container, preventsaging and degradation of the drug over a long period of time with greateffectiveness and helps accomplish the objectives of incorporation ofthe bicarbonate, namely the supply of HCO₃ ⁻, neutralization of thedrug, and assistance in dissolution.

Furthermore, the invention enables the supply of containers for suchstabilized bicarbonate-containing powdery pharmaceutical compositions.

We claim:
 1. A method of stabilizing a bicarbonate-containing powderypharmaceutical composition comprisingfilling the bicarbonate-containingpowdery pharmaceutical composition in a moisture- and gas-permeableplastic container, wrapping the so-filled container in a moisture- andgas-impermeable plastic wrapper and carrying out at least one procedureselected from the group consisting of a procedure of introducing carbondioxide into a space between said container and wrapper, a procedure ofintroducing a carbon dioxide-liberating deoxygenating agent in saidspace and a procedure of introducing a desiccant previously saturatedwith carbon dioxide by way of adsorption in said space.
 2. The methoddefined in claim 1 wherein said carbon dioxide-liberating deoxygenatingagent and desiccant are introduced together in the space between saidcontainer and wrapper.
 3. The method defined in claim 1 wherein saidbicarbonate-containing powdery pharmaceutical composition is a powdereddialysate composition.
 4. The method defined in claim 1 or 2 whereinsaid bicarbonate-containing powdery pharmaceutical composition is anantibiotic-containing composition.
 5. A method of stabilizing abicarbonate-containing powdery pharmaceutical compositioncomprisingfilling said bicarbonate-containing powdery pharmaceuticalcomposition in a moisture- and gas-impermeable plastic wrapper as acontainer and filling carbon dioxide gas in said container.
 6. Themethod defined in claim 5 wherein said bicarbonate-containing powderypharmaceutical composition is a powdered dialysate composition.
 7. Apackage form for insuring a stabilized bicarbonate-containingpharmaceutical composition wherein said package form comprises(1) amoisture- and gas-permeable plastic container accommodating thebicarbonate-containing pharmaceutical composition, (2) a moisture- andgas-impermeable plastic wrapper covering the container and (3) at leastone member selected from the group consisting ofcarbon dioxide, a carbondioxide-liberating deoxygenating agent and a desiccant previouslysaturated with carbon dioxide by way of adsorption, said member beingintroduced in a space between said container and wrapper.
 8. The packageform defined in claim 7 wherein said carbon dioxide-liberatingdeoxygenating agent and desiccant are introduced together in the spacebetween said container and wrapper.
 9. A packaged bicarbonate-containingpowdery pharmaceutical composition comprising a bicarbonate-containingpowdery pharmaceutical composition present in a moisture- andgas-impermeable plastic wrapper as a container filled with carbondioxide.